The present application is related to U.S. Ser. No. 08/059,038, filed May 7, 1993, now U.S. Pat. No. 5,413,999, U.S. Ser. No. 08/163,013 filed Dec. 15, 1993, now abandoned and U.S. Ser. No. 08/170,475 filed Dec. 12, 1993, now abandoned.
The present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as Compound K in the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns a process to effect the synthesis of a substituted furanylpyridylmethylene side chain of a potent HIV protease inhibitor. A halopyridone is coupled with a substituted acetylene to give desired furanyl pyridine product in one or two steps. The process described is superior to prior art in that the process is shorter, more productive, less expensive and has higher yields with less environmental impact.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, Compound J therein, also illustrated in the Examples below.
The present application discloses an improved process to make a furanylpyridylmethylene side chain of the structure ##STR1## which is a new sidechain substituting for the pyridylmethylene group of Compound J. The resulting Compound K requires substantially similar synthesis as Compound J. Compound K is also a potent inhibitor of HIV protease.
Previous attempts to synthesize the furanylpyridyl methylene side chain involved a 10-step synthesis including several high temperature reactions, low overall yields and were difficult to scale-up. The present process reduces the number of steps to one or two, and requires smaller quantities of catalyst, e.g. Cu.sup.II. Also, the present process utilitizes smaller quantities of organic solvents and proceeds in greater overall yield than prior methods, a result providing lower environmental impact than prior methods.